WO2002070068A2 - Analogues de la lipoxine en tant qu'inhibiteurs de l'angiogenese - Google Patents

Analogues de la lipoxine en tant qu'inhibiteurs de l'angiogenese Download PDF

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WO2002070068A2
WO2002070068A2 PCT/US2002/006404 US0206404W WO02070068A2 WO 2002070068 A2 WO2002070068 A2 WO 2002070068A2 US 0206404 W US0206404 W US 0206404W WO 02070068 A2 WO02070068 A2 WO 02070068A2
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inclusive
carbon atoms
epi
branched
lipoxin
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WO2002070068A3 (fr
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Charles N. Serhan
Iolanda M. Fierro
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The Brigham And Women's Hospital
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Priority to DK02721234T priority Critical patent/DK1406698T3/da
Priority to DE60229640T priority patent/DE60229640D1/de
Priority to EP02721234A priority patent/EP1406698B1/fr
Priority to JP2002569237A priority patent/JP2005508282A/ja
Priority to AU2002252175A priority patent/AU2002252175A1/en
Publication of WO2002070068A2 publication Critical patent/WO2002070068A2/fr
Publication of WO2002070068A3 publication Critical patent/WO2002070068A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • TITLE Lipoxin Analogs as Novel Inhibitors of Angiogenesis
  • Angiogenesis is a fundamental process by which new capillaries are formed from existing blood vessels. This process plays important roles in physiological events such as formation of the corpus luteum, development of the embryo and wound healing, including recovery from both myocardial ischemia and peptic ulcer (1). Unregulated growth of blood vessels can contribute to tissue injury in a large number of diseases such as arthritis, diabetes, and tumor progression (2). Endothelial cells are normally quiescent and are activated during the angiogenic response. Upon stimulation, endothelial cells can degrade their basement membrane and proximal extracellular matrix, migrate directionally, then divide and organize into functional capillaries invested by a new basal lamina (3).
  • vascular endothelial growth factor VEGF
  • nonmitogenic factors selected cytokines, CXC chemokines
  • internal peptide fragments of angiostatin and endostatin VEGF
  • VEGF vascular endothelial growth factor
  • Certain eicosanoids also have potent biologic actions on vascular endothelial cells.
  • PGE 2 In rabbits, PGE 2 , PGR 2 ⁇ , and prostacylin (PGI 2 ) stimulate angiogenesis where prostaglandin E series, in particular PGEi, is most potent.
  • PGE 2 is a potent inducer of VEGF expression in synovial fibroblasts.
  • PGI 2 can also induce VEGF gene expression and protein synthesis (4).
  • compositions and methods to prevent angiogenesis that are directed toward the disease process such that angiogenesis is prevented or inhibited physiologically.
  • a need also exists for compositions and methods that induce angiogenesis in tissue that is lacking the requisite or essential physiological requirements for sustainability.
  • ATL Aspirin-triggered lipoxins
  • LXs 15R enantiomeric counterparts of lipoxins
  • LXs, ATLs, and more specifically, the ATL stable analogs, 15-epi-16-(p ⁇ r ⁇ -fluoro)-phenoxy-lipoxin A- t (denoted ATL-1), LXAi, 15-epi- LXA; and 15-R/S-methyl, LXA are potent inhibitors of angiogenesis.
  • ATL-1, LXAi, 15-epi-LXA t and 15-R/S-methyl, LXA_ are potent inhibitors of angiogenesis.
  • VEGF vascular endothelial growth factor
  • ATL-1 inhibited VEGF (3 ng/ml) -induced endothelial cell chemotaxis.
  • ATL-1 treatment (10 ⁇ g/mouse) reduced by -50% the angiogenic phenotype, as assessed by both vascular casting and fluorescence.
  • the present invention pertains to methods for the prevention, reduction or inhibition of angiogenesis.
  • the method is accomplished by the administration of an effective amount of LXA- t and analogs thereof, such as 15-R/S methyl, LXA t , and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • angiogenesis is prevented or inhibited in the subject.
  • the present invention also pertains to methods for the prevention or inhibition of angiogenesis.
  • the method is accomplished by the administration of an effective amount of an aspirin triggered lipoxin (ATL) (15- epi-LXA (such as 15-epi-16-(p ⁇ r ⁇ -fluoro)-phenoxy-lipoxin t (ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • ATL aspirin triggered lipoxin
  • ATL-1 aspirin triggered lipoxin
  • pharmaceutically acceptable salts, esters, amides or prodrugs thereof such as 15-epi-16-(p ⁇ r ⁇ -fluoro)-phenoxy-lipoxin t (ATL-1)
  • angiogenesis is prevented or inhibited in the subject.
  • the present invention pertains to methods for the prevention or inhibition of solid tumor tissue growth undergoing neovascularization in a subject.
  • the method is accomplished by the administration of an effective amount of an aspirin triggered lipoxin (ATL) (15- epi-LXA4, such as 15-epi-16-(p ⁇ ra-fluoro)-phenoxy-lipoxin t (ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof, to a subject in need thereof.
  • ATL aspirin triggered lipoxin
  • the present invention pertains to methods for the prevention or inhibition of solid tumor tissue growth undergoing neovascularization in a subject.
  • the method is accomplished by the administration of an effective amount of LXA and analogs thereof, such as 15- R/S methyl, LXA t , and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • the present invention is directed to methods to inhibit or prevent neovascularization from occurring in a subject.
  • the method is accomplished by the administration of an effective amount of LXA t and analogs thereof, such as 15-R/S methyl, LXA t , and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • the present invention is directed to methods to inhibit or prevent neovascularization from occurring in a subject.
  • the method is accomplished by the administration of an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXA t , such as 15-epi-16-(para-fluoro)-phenoxy-.ipox n A t (ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • ATL aspirin triggered lipoxin
  • the invention is also directed to methods for treating a subject in which neovascularization is occurring in retinal tissue.
  • the neovascularization in the retinal tissue can be prevented or inhibited by administering an effective amount of LXA t and analogs thereof, such as 15-R/S methyl, LXA t , and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • the present invention is further directed to methods for treating a subject in which neovascularization is occurring in retinal tissue.
  • the neovascularization in the retinal tissue can be prevented or inhibited by administering an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXA 4 , such as 15-epi-16- (p ra-fluoro)-phenoxy-lipoxin A 4 (ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • ATL aspirin triggered lipoxin
  • the invention is further directed to methods for treating a subject for restenosis in tissue wherein smooth muscle cell migration occurs following angioplasty.
  • the restenosis can be prevented or inhibited by administering an effective amount of LXAt and analogs thereof, such as 15-R/S methyl, LXA t , and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • the invention is directed to methods for treating a subject for restenosis in tissue wherein smooth muscle cell migration occurs following angioplasty.
  • the restenosis can be prevented or inhibited by administering an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXA t , such as 15-epi-16-(p ⁇ r ⁇ - fluoro)- ⁇ henoxy-lipoxin A 4 (ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • ATL aspirin triggered lipoxin
  • the invention pertains to methods of reducing blood supply to tissue required to support new growth of the tissue in a subject.
  • This reduction or elimination of new undesired growth of tissue can be accomplished by the administration of a composition comprising an effective amount of LXA and analogs thereof, such as 15-R S methyl, LXA t , and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • the invention further pertains to methods of reducing blood supply to tissue required to support new growth of the tissue in a subject.
  • This reduction or elimination of new undesired growth of tissue can be accomplished by the administration of a composition comprising an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXAt , such as 15-epi-16-(p ⁇ ra-fluoro)-phenoxy- lipoxin A t (ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • ATL aspirin triggered lipoxin
  • the present invention pertains to methods for the prevention, diminishment or inhibition the production of new vessels in a subject associated with or stimulated by the production or release of VEGF.
  • the method is accomplished by the administration of an effective amount of a therapeutic agent, including LXA t and analogs thereof, such as 15-R/S methyl, LXAt, and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • a therapeutic agent including LXA t and analogs thereof, such as 15-R/S methyl, LXAt, and pharmaceutically acceptable salts, esters, amides or prodrugs thereof.
  • an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXA t , such as 15-epi-16-(p ⁇ ra-fluoro)-phenoxy-lipoxin A (ATL- 1)
  • ATL aspirin triggered lipoxin
  • pharmaceutically acceptable salts, esters, amides or prodrugs thereof can be utilized.
  • ATL-1 aspirin triggered lipoxin
  • pharmaceutically acceptable salts, esters, amides or prodrugs thereof can be utilized.
  • LXAt LXA t analogs and ATL analogs
  • LXB 4 and LXB 4 analogs pharmaceutically acceptable salts, esters, amides or prodrugs thereof
  • LXB 4 and LXB 4 analogs have the ability to stimulate regeneration and ingrowth of vascular or epithelial tissue in tissues that are in need of such stimulation. This is especially important in tissue grafting, tissue engineering and prosthetic group sites of attachment.
  • Figure 1 demonstrates that ATL-1 inhibits VEGF-stimulated HUVEC proliferation.
  • HUVEC (5 x 10 3 ) were plated in 96-well culture plates and cell proliferation was stimulated with 3 ng/ml VEGF. Three days after treatment, cell numbers were measured using MTT assay. Results are expressed as percent inhibition of proliferation relative to vehicle and represent mean + SE for four independent experiments performed in triplicate.
  • Inset Representative experiment showing the time course of cell proliferation induced by 3 ng/ml (filled triangle) or 10 ng/ml (filled square) VEGF. Vehicle (open circles) and ATL-1 (100 nM) (open triangle).
  • FIG. 2 demonstrates that ATL-1, as well as LXA 4 , 15-epi-LXA t and 15-R/S-methyl, LXA 4 each inhibit endothelial cell chemotaxis.
  • A Chemotaxis was initiated by addition of VEGF (3 ng/ml) or ATL-1 (100 nM) to the lower compartment of a 48-well chemotaxis chamber. Results are expressed as percent of cell migration compared to vehicle alone and represent mean + SE for three independent experiments performed in triplicate (P ⁇ 0.05).
  • B HUVEC were incubated with vehicle or indicated concentrations of ATL-1 (15 min, 37° C) and added to the upper compartment of the microchamber (1 x 10 6 /well).
  • FIG. 1 is a graphical representation demonstrating inhibition of HUVEC proliferation.
  • ATL-1 inhibits LTD 4 -stimulated HUVEC proliferation.
  • HUVECs (5 x 10 3 ) were plated in 96-well culture plates, cell proliferation was stimulated with 10 nM LTD 4 , and cell numbers were determined after 3 days using MTT.
  • B concentration dependent cell proliferation induced by LTD and LTB 4 . Results are expressed as mean ⁇ S.E. for four independent experiments performed in triplicate.
  • FIG. 4 demonstrates that ATL-1 inhibits angiogenic phenotype in vivo.
  • B Cedar wood oil histology of air pouch. Carmine dye vascular casts were made in day-6 air pouch from mice treated locally with vehicle, ATL- 1 (10 ⁇ g), VEGF (1 ⁇ g) or VEGF plus ATL-1. Tissue was fixed in ethanol and cleared in cedarwood oil.
  • Figure 5 depicts Anti-angiogenic action of ATL-1 : fluorescent microscopy. Representative fluorescence photomicrographs showing the anti- angiogenic action of ATL-1 (10 ⁇ g/pouch) in the murine air pouch (see methods).
  • Figure 6 are photomicrographs of a murine air pouch.
  • ASA aspirin
  • ATL aspirin- triggered 15-epi-lipoxins
  • ATL-1 15-epi-16-(p ⁇ ra-fluoro)-phenoxy-lipoxin A
  • COX cyclooxygenase
  • HETE hydroxyeicosatetraenoic acid
  • HUVEC human umbilical vein endothelial cells
  • IL interleukin
  • LO lipoxygenase
  • LT leukotriene
  • LX lipoxin
  • LXA t 55, 6R, 155-trihydroxy-7, 9, 13-trans-l -cis- eicosatetraenoic acid
  • 15-epi-LXA t 55, 6R, 15R-trihydroxy-7,9, 13-tr ⁇ s- 11 -cz ' s- eicosatetraenoic acid
  • 15-R/5 aspirin
  • ATL aspirin- triggered 15-epi-lipoxi
  • the hydroxyl(s) of ATLs, LXAjS, and LXB 4 s can be protected by various protecting groups, such as those known in the art.
  • An artisan skilled in the art can readily determine which protecting group(s) can be useful for the protection of the hydroxyl group(s). Standard methods are known in the art and are more fully described in literature.
  • suitable protecting groups can be selected by the skilled artisan and are described in Green and Wuts, "Protecting Groups in Organic Synthesis", John Wiley and Sons, 1991 , the teachings of which are incorporated herein by reference.
  • Preferred protecting groups include TMS or TIPPS groups, and preferably acetate or proprionate groups.
  • one or more hydroxyl groups can be treated with a mild base, such as triethylamine in the presence of an acid chloride or silyl chloride to facilitate a reaction between the hydroxyl ion and the halide.
  • a mild base such as triethylamine
  • an alkyl halide can be reacted with the hydroxyl ion (generated by a base such as lithium diisopropyl amide) to facilitate ether formation.
  • hydroxyl groups need be protected.
  • One, two or all three hydroxyl groups can be protected. This can be accomplished by the stoichiometric choice of reagents used to protect the hydroxyl groups. Methods known in the art can be used to separate the mono, di- or tri-protected hydroxy compounds, e.g., HPLC, LC, flash chromatography, gel permeation chromatography, crystallization, distillation, etc.
  • One advantage of protecting one or more hydroxyl groups of ATL, LXA , or LXB 4 compounds, e.g., via acetates, is the ability to delay the complete metabolic uptake of the compound(s). This is one means by which the compound(s) can remain active over a prolonged period of time as the subject's body slowly removes the protecting group from the hydroxyl under normal physiological conditions. Additionally, by protecting one or more of the hydroxyl groups of these compounds, hydrolysis of the protecting group allows the medication to enter the biochemical pathway of the subject prior to degradation of the parent, unprotected, compound.
  • Aspirin's therapeutic mechanism of action includes inhibition of COX- derived prostanoids (10). It was discovered that COX-2, when acetylated by ASA, blocks the ability of COX-2 to generate prostanoids, yet this enzyme remains active in endothelial cells, epithelial cells and mononuclear cells and initiates the biosynthesis of new products of cell-cell interactions or transcellular biosynthesis termed aspirin-triggered- 15-epi-lipoxins (ATLs) (11). These novel endogenous lipid mediators are the carbon 15 epimers of LX that carry their 15 alcohol in the R configuration compared to their native lipoxin (LX) counterparts and appear to mimic most if not all endogenous LX bioactivi ⁇ es.
  • Both LX and ATL actions include inhibiting adhesion and transmigration of neutrophils, and hence can serve as counterregulatory signals to limit and/or regulate leukocyte accumulation that are potentially operative in the dampening and resolution of inflammatory sites (14).
  • LXAt and ATL stable analogs of both lipoxins, i.e., LXAt and ATL were designed that enhance bioavailabilities and these natural compounds bioactivities compared to their native products (14) and also proved to be -100 times the potency of ASA (13).
  • the present invention establishes that LXA- t s and ATLs can regulate angiogenesis, a previously unknown and surprising application of these compounds.
  • ATLs and LXAt compounds including, 15-epi-LXA t or 15-R/5-methyl, LXA t and LXA4 proved to be potent angiostatic eicosanoid in vivo, identifying a new activity for these endogenous mediators that is in sharp contrast to the actions of other eicosanoids and is relevant in several human diseases.
  • the present invention pertains to methods for the prevention, diminishment or inhibition of angiogenesis.
  • the method is accomplished by the administration of an effective amount of LXA and analogs thereof, such as 15-R/S methyl, LXA t , and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • angiogenesis is prevented, reduced or inhibited in the subject.
  • the therapeutic agents can be used in the treatment of the disease states and conditions of the angiogenic disease processes as described below.
  • LXAt and ATL therapeutic compounds described throughout the specification can be used for the treatment of restenosis, solid tumor tissue growth, neovascularization, e.g., retinal tissue, and reducing blood supply to tissue required to support new growth of tissue in a subject.
  • the present invention also pertains to methods for the prevention, reduction or inhibition of angiogenesis in tissue of a subject.
  • the method is accomplished by the administration of an effective amount of an aspirin triggered lipoxin (ATL) (15-epi-LXA t, such as 15-epi-16-(p ⁇ ra-fluoro)- phenoxy-lipoxin A 4 (ATL-1)), and pharmaceutically acceptable salts, esters, amides or prodrugs thereof, to a subject in need thereof.
  • ATL aspirin triggered lipoxin
  • ATL-1 aspirin triggered lipoxin
  • angiogenesis is prevented or inhibited in the subject.
  • the invention thus provides for a method for the general inhibition of angiogenesis in tissue, and thereby inhibits or prevent events in the tissue which depend upon angiogenesis.
  • the method comprises administering to the tissue a composition comprising an angiogenesis-inhibiting amount of, for example, ATL-1, LXAt, 15-epi-LXAt or 15-R S-methyl, LXA t .
  • angiogenesis means the formation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans or animals only undergo angiogenesis in very specific restricted situations. For example, angiogenesis is associated with wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. The biochemical aspects of angiogenesis are associated with a highly regulated system of angiogenic stimulators and inhibitors. Controlled angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to the uncontrolled angiogenesis.
  • Endothelial cells and pericytes surrounded by a basement membrane, form capillary blood vessels. Erosion of the basement membrane promotes angiogenesis by enzymes released by endothelial cells and leukocytes.
  • the endothelial cells which line the lumen of blood vessels, then break through the basement membrane.
  • Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane.
  • the migrating cells form an offshoot from the parent blood vessel, where the endothelial cells undergo mitosis and proliferate.
  • the endothelial offshoots can merge with each other to form capillary loops, creating a new blood vessel. In the disease state, prevention of angiogenesis could avert the damage caused by the invasion of the new microvascular system.
  • Persistent, unregulated angiogenesis can occur in a multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions.
  • the diverse pathological states created due to unregulated angiogenesis have been grouped together as angiogenic dependent or angiogenic associated diseases.
  • the present invention provides therapies that are directed to control the angiogenic processes thus leading to the abrogation or mitigation of these diseases. With the exception of traumatic wound healing, corpus leuteum formation and embryogenesis, it is believed that angiogenesis processes are associated with undesired, and often life threatening, disease processes and therefore, the use of the present therapeutic methods are selective for the disease, i.e., angiogenesis, and do not have deleterious side effects.
  • angiogenic diseases can be treated according to the present invention by use of the afore-mentioned ATLs, such as ATL-1 or LXA t s such asl5-R/5-methyl, LXA 4 .
  • ATLs such as ATL-1 or LXA t s such asl5-R/5-methyl, LXA 4 .
  • LXA t s such asl5-R/5-methyl, LXA 4 .
  • ocular neovascular disease This disease is characterized by invasion of new blood vessels into the structures of the eye such as the retina or cornea. It is perhaps, one of the most common causes of blindness and is involved in over twenty eye diseases. For example, in age-related macular degeneration, the associated visual problems are caused by an ingrowth of chorioidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia.
  • corneal neovascularization include, but are not limited to, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, epidemic keratoconjunctivitis, pterygium keratitis sicca, sjogrens, acne rosacea, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, phylectenulosis, syphilis, Mycobacteria infections, Herpes simplex infections, Herpes zoster infections, Wegeners sarcoidosis, Scleritis, Steven's Johnson syndrome, periphigoid radial keratotomy, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, marginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, and corneal graph rejection.
  • Diseases associated with retinal/choroidal neovascularization include, but are not limited to, diabetic retinopathy, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Pagets disease, retinopathy of prematurity, Eales disease, Bests disease, myopia, optic pits, Stargarts disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, Bechets disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, trauma and post-laser complications.
  • diseases include, but are not limited to, diseases associated with rubeosis and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy.
  • An even more prevalent disease in which angiogenesis is believed to be involved is rheumatoid arthritis.
  • the blood vessels in the synovial lining of the joints undergo angiogenesis.
  • the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction. It is believed that the factors involved in angiogenesis can actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis.
  • the present invention provides therapeutic intervention that prevents the bone destaiction and can halt the progress of the disease and provide relief for persons suffering with arthritis.
  • Bartonellosis can result in a chronic stage that is characterized by proliferation of vascular endothelial cells.
  • An even more insidious pathological role associated with angiogenesis is found in arteriosclerosis.
  • the plaquing of the lumen of blood vessels has been shown to have angiogenic stimulatory activity.
  • a frequent angiogenic disease of childhood is hemangioma.
  • the tumors associated with the disease are benign and regress without intervention. In more severe cases, the tumors grow and create clinical complications.
  • Systemic forms of hemangiomas, the hemangiomatoses have a high mortality rate. Therapy-resistant hemangiomas exist that cannot be treated with therapeutics currently in use.
  • Angiogenesis is also responsible for damage found in hereditary diseases such as Osier- Weber-Rendu disease, or hereditary hemorrhagic telangiectasia. These diseases are characterized by multiple small angiomas, tumors of blood or lymph vessels. The angiomas are found in the skin and mucous membranes, often accompanied by epistaxis (nosebleeds) or gastrointestinal bleeding and sometimes with pulmonary or hepatic arteriovenous fistula. Of great concern is the disease state(s) associated with cancer(s). Often times, the cancer is associated with angiogenesis and is identified by solid tumor formation and metastasis.
  • Angiogenic factors are associated with several solid tumors such as neuroblastoma, rhabdomyosarcomas, retinoblastoma, Ewing sarcoma, and osteosarcoma. It is known that a tumor cannot expand without a blood supply to provide nutrients and remove cellular wastes. Tumors in which angiogenesis is important include solid tumors, and benign tumors such as acoustic neuroma, neurofibroma, trachoma and granulomas. Prevention or inhibition of angiogenesis could prevent or halt the growth of these tumors and the subsequent degenerative condition due to the presence of the tumor.
  • Angiogenesis has also been associated with blood-born tumors including leukemias, any of the various acute or chronic neoplastic diseases of bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen. It is believed that angiogenesis is significant as a caustive factor in the abnormalities in the bone marrow that give rise to leukemialike tumors.
  • Angiogenesis is important in two stages of tumor metastasis.
  • the first stage where angiogenesis stimulation is important is in the vascularization of the tumor which allows tumor cells to enter the blood stream and to circulate throughout the body. Once the tumor cells leave the primary site, and find a secondary metastasis site, angiogenesis must occur before the new tumor can grow and expand. Therefore, prevention of angiogenesis could prevent metastasis of tumors and contain the neoplastic growth at the primary site.
  • the present invention can be used in combination with other therapies such as conventional chemotherapy directed against solid tumors and metastases.
  • ATLs such as ATL-1 or LXA ⁇ t s, such as 15-R S-methyl, LXA 4 , can be administered during or after chemotherapy.
  • the drug should be administered when the tumor tissue is responding to the toxic assault when vascular tissue is being reorganized to supply blood and nutrients to the tumor tissue.
  • ATLs such as ATL-1 or LXAts can be used as a phrophylatic treatment after surgical removal of a tumor to prevent angiogenesis from occurring at the treatment site.
  • Knowledge of the role of angiogenesis in the maintenance and metastasis of tumors has led to a prognostic indicator for breast cancer.
  • the amount of neovascularization found in the primary tumor was determined by counting the microvessel density in the area of the most intense neovascularization in invasive breast carcinoma. A high level of microvessel density was found to correlate with tumor recurrence. Control of angiogenesis by therapeutic means could possibly lead to cessation of the recurrence of the tumors.
  • Angiogenesis is also involved in normal physiological processes such as reproduction and wound healing. Angiogenesis is an important step in ovulation and also in implantation of the blastula after fertilization. Prevention of angiogenesis could be used to induce amenorrhea, to block ovulation or to prevent implantation by the blastula.
  • Restenosis is a process of smooth muscle cell (SMC) migration and proliferation at the site of percutaneous transluminal coronary angioplasty which hampers the success of angioplasty.
  • SMC smooth muscle cell
  • the migration and proliferation of SMCs during restenosis can be considered a process of angiogenesis which is inhibited by the present methods. Therefore, the invention also contemplates inhibition, reduction or prevention of restenosis by inhibiting, reducing or preventing angiogenesis according to the present methods in a subject following angioplasty procedures.
  • an ATL such as ATL-1 or an LXA 4 , such as 15-R/S-methyl, LXA t
  • an ATL can be administered, preferably via intravenous injection, several days before the operation or after the angioplasty procedure for from about 2 to about 28 days, and more typically for about the first 14 days following the procedure.
  • subject refers to any living organism in which an angiogenic response is elicited.
  • subject includes, but is not limited to, humans, nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs, and the like.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • mammal refers to a living organism capable of eliciting an immune response to an antigen.
  • subject includes, but is not limited to, nonhuman primates such as chimpanzees and other apes and monkey species, sheep, pigs, goats, horses, dogs, cats, mice, rats and guinea pigs, and the like.
  • salts refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
  • These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • These can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S. M., et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1-19 which is incorporated herein by reference).
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.CS. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
  • a prodrug is a compound that, upon in vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes.
  • the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • the compounds of the invention can be formulated into pharmaceutical compositions as described, vide infra.
  • the compound can be administered over an extended period of time in a sustained release composition.
  • Sustained release compositions are known in the art and one skilled in the art can formulate an acceptable composition based on generally recognized parameters in the art.
  • the glycerol ester can be used in the treatment of inflammatory conditions, described herein, in sustained release compositions, i.e., a transdermal patch, as known in the art. Suitable methods to prepare a transdermal patch can be found in U.S. Patent No., 5,814,599, 5,846,974 or 4,201 ,211 , the contents of which are incorporated herein by reference.
  • the compounds can be delivered transdermally using the types of patch technologies available from Ciba-Geigy Corporation and Alza Corporation.
  • the administration of the pharmaceutical compositions of the present invention can be intermittent, or at a gradual, continuous, constant or controlled rate to a warm-blooded animal, such as a human being.
  • the time of day and the number of times per day that the pharmaceutical formulation is administered can vary. Administration preferably is such that the active ingredients of the pharmaceutical formulation interact with the inflammatory condition.
  • a “therapeutically effective amount” is an amount of an ATL, such as ATL-1 or an LXA 4 , such as 15-R S-methyl, LXA 4 , sufficient to produce a measurable inhibition, reduction or prevents angiogenesis in the tissue being treated, i.e., an angiogenesis-inhibiting amount.
  • Inhibition of angiogenesis can be measured in situ by immunohistochemistry or by other methods known to one skilled in the art such as measurement by FAC analysis that monitors P-selectin or VEGF receptors. See also Figures 4 and 5.
  • the pharmaceutical compositions of the invention can include a "therapeutically effective amount” or a “prophylactically effective amount” of an antiangiogenic of the invention.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, e.g., a diminishment, reduction or prevention of angiogenic factors associated with various disease states or conditions.
  • a therapeutically effective amount of the antiangiogenic can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antiangiogenic to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, i.e. prevent. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • Dosage regimens can be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of an antiangiogenic of the invention is 0.1-20 mg/kg, more preferably 1-10 mg/kg. It is to be noted that dosage values can vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition,
  • antiangiogenic compounds of the invention e.g., an ATL, such as
  • ATL-1 or an LXAt, such as 15-R/5-methyl, LXA t can be incorporated into pharmaceutical compositions suitable for administration to a subject.
  • the pharmaceutical composition comprises an antiangiogenic of the invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers can further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antiangiogenic.
  • the mono-, di- and/or tri- protected alcohols of the compounds of the invention provide for sustained release of the inhibitory/preventative compound.
  • the tri-acyl analogs of the invention provide for such a sustained release of the hydrolyzed tri-hydroxy alcohol(s). The triacylated analogs are thus de-esterified in the blood of the subject.
  • the antiangiogenics of the invention can be incorporated into a pharmaceutical composition suitable for parenteral administration.
  • suitable buffers include but are not limited to, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate.
  • Sodium chloride can be used to modify the toxicity of the solution at a concentration of 0-300 mM (optimally 150 mM for a liquid dosage form).
  • Cryoprotectants can be included for a lyophilized dosage form, principally 0-10% sucrose (optimally 0.5-1.0%).
  • Other suitable cryoprotectants include trehalose and lactose.
  • Bulking agents can be included for a lyophilized dosage form, principally 1-10% mannitol (optimally 2-4%).
  • Stabilizers can be used in both liquid and lyophilized dosage forms, principally 1- 50 mM L-Methionine (optimally 5-10 M).
  • Other suitable bulking agents include glycine, arginine, can be included as 0-0.05% polysorbate-80 (optimally 0.005-0.01%).
  • Additional surfactants include but are not limited to polysorbate 20 and BRIJ surfactants.
  • compositions of this invention can be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans.
  • the preferred mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antiangiogenic is administered by intravenous infusion or injection.
  • the antiangiogenic is administered by intramuscular or subcutaneous injection.
  • the antiangiogenic is administered orally.
  • a preferred embodiment includes the use of the compounds of the invention in eye-drop solutions. This provides for application to the ease to inhibit or prevent ocular diseases such as glaucoma.
  • the active ingredient i.e., the compounds of the invention, would be dissolved in an aqueous solution that can be applied directly to the eye.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, dispersion, Hposome, or other ordered structure suitable to high drug concentration.
  • Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antigen, antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and spray-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • the antiangiogenics of the present invention can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
  • the active compound can be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g. , Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • an antiangiogenic of the invention can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the compound (and other ingredients, if desired) can also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the compounds can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • it can be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
  • the present invention also provides for packaged pharmaceutical compositions useful in the prevention or inhibition of angiogenic activity in a subject.
  • the packaged pharmaceutical composition includes a container holding a therapeutically effective amount of at least one ATL, such as ATL-1 or an LXA t , such as 15-R S-methyl, LXA 4 , or a pharmaceutically acceptable salt, esters, amide, or prodrug thereof and instructions for using the therapeutic compound for preventing, reducing or inhibiting angiogenic activity in the subject.
  • the present invention provides therapeutically effective amounts of packaged pharmaceutical compositions, e.g., ATL-1, LXA 4 , 15-epi- LXAt or 15-R/S-methyl, LXA 4 or pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, and instructions useful to treat, i.e., inhibit or prevent, solid tumor tissue growth from undergoing neovascularization, neovascularization from occurring, neovascularization from occurring in retinal tissue, restenosis from occurring following angioplasty in a tissue wherein smooth muscle cell migration occurs, or reducing blood supply to a tissue required to support new growth of new angiogenic tissue.
  • the present invention also provides angeogenic compounds that facilitate angiogenesis.
  • LXAt, LXA analogs and ATL analogs, LXB 4 and LXB 4 analogs and pharmaceutically acceptable salts, esters, amides or prodrugs thereof provide the opposite effects with regard to revascularization of tissue by the above-identified compounds of the invention. That is, it has been surprisingly discovered that LXB 4 and LXB 4 analogs have the ability to stimulate regeneration and ingrowth of vascular or epithelial tissue in tissues that are in need of such stimulation. This is especially important in tissue grafting, tissue engineering and prosthetic group sites of attachment. Therefore, the present invention provides methods of tissue regeneration, compounds for such application and packaged pharmaceuticals to accomplish such results.
  • cardiovascular disease occurs as a consequence of the partial or complete blockage of vessels carrying blood in the coronary vascular system and in peripheral vasculature. Occlusion of the vessel can results in death of tissue previously nourished by the occluded vessels or inability of the vessels to transport sufficient blood supply to regions requiring high blood consumption and accompanying nutrients. Blood vessel occlusion can be partially compensated by the natural process of angiogenesis, in which new conduits are formed to replace the function of the impaired vessels. These new conduits are referred to as "collateral" vessels and can help in the restoration of blood flow to the deprived tissue, thereby constituting natural bypasses around the occluded vessels. However, some individuals for various reasons are unable to generate sufficient collateral vessels to manage the consequences of diminished blood flow from cardiovascular disease.
  • the LXB 4 compounds of the invention can be used to enhance the body's natural ability to repair itself by undergoing natural angiogenesis. As can be seen from the contents of the specification and Figures, vessel growth is stimulated by these unique compounds. This process and use of the present compounds can be utilized for the treatment of wounds. The LXB 4 compounds help stimulate the healing process, causing re-epithelialization and vascularization to occur.
  • Suitable lipoxin analogs including ATLs, LXA 4 s and LXB s encompassed by the present invention include those having the following characteristics.
  • R 2 can be
  • the lipoxin analogs of this invention have the following structural formula I:
  • X is Ri, OR.i, or SRf, wherein Ri is
  • R a Q a R b wherein Q a is O or S; wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
  • the lipoxin analogs have the following structure II:
  • X is R 1 ⁇ ORi, or SRi ; wherein Ri is (i) a hydrogen atom;
  • R a Q 2 R b wherein Q 2 is -O- or -S-; wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched; wherein 4 is
  • the lipoxin analogs have the following structure III:
  • X is R ls ORi, or SRi ; wherein Ri is
  • R a Q 2 R b wherein Q 2 is -O- or -S-; wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched; wherein ⁇ is
  • R 5 is (a) an alkyl of 1 to 9 carbon atoms which can be straight chain or branched;
  • R a Q a R b wherein Q a is -O- or -S-; wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched; or
  • lipoxin analogs have the following structural formula IV:
  • X is Rj, ORi, or SRi ; wherein Ri is (i) a hydrogen atom;
  • R a Q 2 R b wherein Q 2 is -O- or-S-; wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched; wherein R is
  • haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched; and wherein R 6 is (a) a hydrogen atom; (b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched; or
  • lipoxin analogs have the following structural formula V:
  • Ri is (i) a hydrogen atom
  • R a Q 2 R b wherein Q 2 is -O- or -S-; wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched; wherein Y j or Y 2 is -OH, methyl, hydrogen, or — SH and wherein the other is (a) a hydrogen atom;
  • haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched.
  • lipoxin analogs have the structural formula VI:
  • lipoxin analogs have the following structural formula VII:
  • the lipoxin analogs have the structural formula VIII:
  • R b and R c are each independently: (a) a hydrogen atom; (b) a hydroxyl or a thiol;
  • Rd and R e are each independently:
  • the lipoxin analogs have the structural formula IX:
  • the compounds have the structural formula X:
  • the compounds have the structural formula XI:
  • R a is (i) a hydrogen atom; (ii) an alkyl of 1 to 8 carbons atoms, inclusive, which can be straight chain or branched; or
  • R a Q 2 R b wherein Q 2 is — O — or — S — ; wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched; wherein Y is — OH, methyl, or — SH; wherein Y 2 is
  • Z,, Z n , Z, n , Z] V and Z v are each independently selected from ⁇
  • N0 2 , -CN, -C( 0)-R ⁇ , -SO3H, a hydrogen atom, halogen, methyl, -OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
  • Z 1; Zdon, Z m , Z, v and Z v are each independently selected from -
  • Zj through Z v are as defined above; (d) a haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched.
  • the compounds of this invention have the following structural formulas:
  • R' is H or CH 3 ; and where the substituents at C* are in the R configuration.
  • the compounds of this invention have the following structural formulas:
  • LXB 4 or the C5 and C14 and C15 alkanoates (acetates) of LXB 4 may be excluded.
  • lipoxins and lipoxin analogs useful as therapeutic agents in the treatment of the maladies, disease states or conditions described throughout the specification has the formula:
  • T is O or S, and pharmaceutically acceptable salts thereof.
  • lipoxins and lipoxin analogs useful as therapeutic agents in the treatment of the maladies, disease states or conditions described throughout the specification has the formula:
  • X is Ri, ORi, or SRi; wherein Ri is
  • R a Q 2 R b wherein Q 2 is -O- or -S-; wherem R a is alkylene of 0 to 6 carbon atoms, inclusive, which may be straight chain or branched and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b is 0, then R b is a hydrogen atom; wherein R is
  • lipoxins and lipoxin analogs useful as therapeutic agents in the treatment of the maladies, disease states or conditions described throughout the specification has the formula:
  • R a Q 2 R b wherein Q 2 is -O- or -S-; wherein R a is alkylene of 0 to 6 carbon atoms, inclusive, which may be straight chain or branched and wherein R is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b is 0, then R b is a hydrogen atom; wherein R 4 is
  • lipoxins and lipoxin analogs useful as therapeutic agents in the treatment of the maladies, disease states or conditions described throughout the specification has the formula:
  • X is Ri, ORj, or SR,; wherein Rj is
  • T is O or S, and pharmaceutically acceptable salts thereof.
  • lipoxins and lipoxin analogs useful as therapeutic agents in the treatment of the maladies, disease states or conditions described throughout the specification has the formula:
  • X is Ri, ORi, or SRi; wherein Ri is
  • R 5 para-fluorophenyl and/or unsubstituted phenyl are preferred, e.g., 15-epi-16-(para-fluoro)-phenoxy- LXA 4 , 16-(para-fluoro)-phenoxy-LXA 4 , 15-epi-16-phenoxy-LXAt or 16- phenoxy-LX t .
  • the present invention is directed to pharmaceutical compositions including compounds having the formulae described throughout the specification and a pharmaceutically acceptable carrier.
  • a preferred compound is
  • Qi is a carbonyl
  • X is a hydroxyl or an -OR, wherein R is an alkyl group, i.e., methyl or ethyl groups, and R 4 is a hydrogen atom.
  • Yi is a hydroxyl and the carbon bearing the hydroxyl can have an R or S configuration.
  • the chiral carbon bearing the hydroxyl group e.g., Yi, is designated as a 15-epi- lipoxin as is known in the art.
  • the chirality of the carbons bearing the R 2 , R 3 , Q 3 and Q 4 groups can each independently be either R or S.
  • Q 3 and Q 4 have the chiralities shown in above-referenced structures.
  • t is a hydrogen.
  • R 6 is a hydrogen.
  • R 5 can be a substituted or unsubstituted, branched or unbranched alkyl group having between 1 and about 6 carbon atoms, preferably between 1 and 4 carbon atoms, most preferably between 1 and 3, and preferably one or two carbon atoms.
  • the carbon atoms can have substituents which include halogen atoms, hydroxyl groups, or ether groups.
  • the compounds useful in the present invention can be prepared by the following synthetic scheme:
  • the acetylenic fragment can be prepared by the methods discussed in Nicolaou, K.C. et al. (1991) Angew. Chem. Int. Ed. Engl. 30:1100; Nicolaou, K.C. et al. (1989) J. Org. Chem. 54:5527; Webber, S.E. et al. (1988) Adv. Exp. Med. Biol. 229:61; and U.S. Patent 5,441,951.
  • the second fragment can be prepared by the methods of Raduchel, B. and Vorbruggen, H. (1985) Adv. Prostaglandin Thromboxane Leukotriene Res.
  • acetylenic intermediates are also encompassed by the present invention as being useful for the treatments of the various maladies described herein. Similar approaches can be taken to produce LXB 4 acetylenic compounds as described in, for example, US Patent No. 6,316,648.
  • a “lipoxin analog” shall mean a compound which has an "active region” that functions like the active region of a "natural lipoxin", but which has a “metabolic transformation region” that differs from natural lipoxin.
  • Lipoxin analogs include compounds which are structurally similar to a natural lipoxin, compounds which share the same receptor recognition site, compounds which share the same or similar lipoxin metabolic transformation region as lipoxin, and compounds which are art-recognized as being analogs of lipoxin.
  • Lipoxin analogs include lipoxin analog metabolites.
  • the compounds disclosed herein may contain one or more centers of asymmetry. Where asymmetric carbon atoms are present, more than one stereoisomer is possible, and all possible isomeric forms are intended to be included within the structural representations shown.
  • Optically active (R) and (S) isomers may be resolved using conventional techniques known to the ordinarily skilled artisan. The present invention is intended to include the possible diastereiomers as well as the racemic and optically resolved
  • corresponding lipoxin and "natural lipoxin” refer to a naturally-occurring lipoxin or lipoxin metabolite.
  • an analog has activity for a Iipoxin-specific receptor
  • the corresponding or natural lipoxin is the normal ligand for that receptor.
  • an analog is a LXA t specific receptor on differentiated HL-60 cells
  • the corresponding lipoxin is LXA 4 .
  • an analog has activity as an antagonist to another compound (such as leukotriene C4 and/or leukotriene D4), which is antagonized by a naturally- occurring lipoxin, that natural lipoxin is the corresponding lipoxin.
  • Active region shall mean the region of a natural lipoxin or lipoxin analog, which is associated with in vivo cellular interactions.
  • the active region may bind the "recognition site" of a cellular lipoxin receptor or a macromolecule or complex of macromolecules, including an enzyme and its cofactor.
  • lipoxin A 4 analogs have an active region comprising C 5 — C 15 of natural lipoxin A 4 .
  • lipoxin B analogs have an active region comprising C5-C14 of natural lipoxin B 4 .
  • a receptor may be isolated, on an intact or permeabilized cell, or in tissue, including an organ.
  • a receptor may be from or in a living subject, or it may be cloned.
  • a receptor may normally exist or it may be induced by a disease state, by an injury, or by artificial means.
  • a compound of this invention may bind reversibly, irreversibly, competitively, noncompetitively, or uncompetitively with respect to the natural substrate of a recognition site.
  • metabolic transformation region is intended to refer generally to that portion of a lipoxin, a lipoxin metabolite, or lipoxin analog including a lipoxin analog metabolite, upon which an enzyme or an enzyme and its cofactor attempts to perform one or more metabolic transformations which that enzyme or enzyme and cofactor normally transform on lipoxins.
  • the metabolic transformation region may or may not be susceptible to the transformation. Similarly, such regions are possibly located within ATL and LXB analogs.
  • a nonlimiting example of a metabolic transformation region of a lipoxin is a portion of LXAt that includes the C- 13, 14 double bond or the C-15 hydroxyl group, or both.
  • detectable label molecule is meant to include fluorescent, phosphorescent, and radiolabeled molecules used to trace, track, or identify the compound or receptor recognition site to which the detectable label molecule is bound.
  • the label molecule may be detected by any of the several methods known in the art.
  • labeled analog is further understood to encompass compounds which are labeled with radioactive isotopes, such as but not limited to tritium ( H), deuterium ( 2 H), carbon ( 14 C), or otherwise labeled (e.g. fluorescently).
  • radioactive isotopes such as but not limited to tritium ( H), deuterium ( 2 H), carbon ( 14 C), or otherwise labeled (e.g. fluorescently).
  • the compounds of this invention may be labeled or derivatized, for example, for kinetic binding experiments, for further elucidating metabolic pathways and enzymatic mechanisms, or for characterization by methods known in the art of analytical chemistry.
  • inhibitors metabolism means the blocking or reduction of activity of an enzyme which metabolizes a native eicosanoid.
  • the blockage or reduction may occur by covalent bonding, by irreversible binding, by reversible binding which has a practical effect of irreversible binding, or by any other means which prevents the enzyme from operating in its usual manner on another lipoxin analog, including a lipoxin analog metabolite, a lipoxin, or a lipoxin metabolite.
  • this also applies to ATL and LXB 4 analogs.
  • resists metabolism is meant to include failing to undergo one or more of the metabolic degradative transformations by at least one of the enzymes which metabolize lipoxins, ATL or LXB analogs.
  • LXA t analog that resists metabolism are 1) a structure which can not be oxidized to the 15-oxo form, and 2) a structure which may be oxidized to the 15-oxo form, but is not susceptible to enzymatic reduction to the 13,14-dihydro form.
  • LXA 4 analog which more slowly undergoes metabolism is a structure which has a higher transition state energy for C-15 dehydrogenation than does LXA t because the analog is sterically hindered at the C-16.
  • tissue is intended to include intact cells, blood, blood preparations such as plasma and serum, bones, joints, muscles, smooth muscles, and organs.
  • halogen is meant to include fluorine, chlorine, bromine and iodine, or fluoro, chloro, bromo, and iodo.
  • Human umbilical vein endothelial cells were isolated by 0.1% collagenase digestion (Worthington Biochemical, Bedford, MA) and propagated on gelatin-coated (0.1%) tissue culture plates in medium 199 (Gibco BRL, Grand Island, NY) supplemented with 20% heat-inactivated fetal bovine serum (BioWhittaker, Walkersville, MD), 50 ⁇ g/ml of endothelial cell mitogen (Biomedical Technologies, Stoughton, MA), 8 U/ml heparin (APP, Los Angeles, CA), 50 U/ml penicillin and 15 ⁇ g/ml streptomycin. Only passages 2 and 3 were used in reported experiments. Endothelial Cell Proliferation
  • HUVEC 5xl0 3
  • HUVEC 5xl0 3
  • the medium was removed and replaced with fresh medium 199 supplemented with 5% fetal bovine serum and different concentrations of recombinant human VEGF16 5 (R&D Systems, Minneapolis, MN), LTD 4 or LTB .
  • Endothelial cells were enumerated after 72 h using the MTT® assay (Sigma, St. Louis, MO) (15).
  • ATL-1 was prepared as in Clish et al. (13).
  • Percent inhibition was evaluated in a similar manner and included a 15 minute incubation (37° C) with 15-epi-lipoxin At, 15-epi-16-(p ra-fluoro)- phenoxy-lipoxin A methyl ester (ATL-1), LXA t , 15-epi-LXAt or 15-R/S- methyl, LXA t prior to the addition of agonists. All incubations were performed in triplicate. Before each experiment the integrity and concentration of ATL-1, LXA t , 15-epi-LXA 4 or 15-R S-methyl, LXA 4 was assessed by physical methods including LC/MS/MS and UV (13).
  • VEGF, ATL-1 or vehicle were added to the lower wells of a 48-well chemotaxis chamber (NeuroProbe, Cabin John, MD). The wells were overlaid with a 10 ⁇ m pore size polycarbonate filter coated with 0.1 % gelatin. HUVEC (1x10°) were placed in the upper wells and the chamber was incubated (37°C, 5% CO 2 for 12 h). Following incubations, filters were removed, scraped of cells from the upper surface, fixed and stained with Diff-Quik (Dade Behring, Newark, DE). Cells that migrated across the filter toward the lower surface were enumerated by light microscopy; four fields were counted at high magnification (100X). Incubations were performed in triplicate. To assess inhibition, endothelial cells were suspended in media with vehicle or ATL-1 for 15 min before placement in the chamber.
  • DNA fragmentation in individual apoptotic cells was quantitated using a photometric enzyme immunoassay (Apotosis detection kit: R&D Systems).
  • Angiogenesis was assessed with murine air pouches that were raised via subcutaneous injection of sterile air (3 ml) beneath the dorsal skin of anesthetized mice (BALB/c, male 6-8 wk). After 24 hrs, ATL-1 (10 ⁇ g/pouch) or vehicle was delivered locally, immediately before the injection of VEGF (1 ⁇ g/pouch). The vascular content was assessed by the formation of vascular casts (as in 16). Briefly, mice were anesthetized (at 144 h) and peripheral vasodilation was raised by placing the animals in a heated jacket (40° C, 10 min). Vascular casts were formed by the i.v.
  • mice were anesthetized and injected i.v. with 200 ⁇ l of 0.05 g/ml fluorescein isothiocyanate-dextran (Sigma) in PBS at 144 h immediately before sacrifice. Dissected linings were fixed, mounted on glass slides and examined for fluorescence (Nikon Eclipse model E600). In both protocols, the observers were not blinded to the treatments.
  • Air pouch membranous tissues were fixed in 10% buffered formalin overnight and processed for paraffin embedding.
  • Five-micrometer paraffin sections of membrane tissue cut on face were used for immunohistochemistry for CD31 expression. Briefly, slides were deparaffinized and pretreated in 0.25% trypsin (Sigma Chemical) for 20 min at 37° C, followed by washing in distilled water. All further steps were performed at room temperature in a hydrated chamber. Slides were pretreated with Peroxidase Block (DAKO, Carpinteria, CA) for 5 min to quench endogenous peroxidase activity, followed by a 1 :5 dilution of goat serum in 50 Mm Tris-CI, pH 7.4, for 20 min to block nonspecific binding sites.
  • DAKO Peroxidase Block
  • Results are presented as means ⁇ S.E.M. Statistical evaluation of the results was performed by analysis of variance, and values of P ⁇ 0.05 were taken to represent statistically significant differences between group means.
  • ATL-1 In sharp contrast, LXB stable analogs increased proliferation. Because these are related structures, the separate actions of ATL and LXB analogs with these cells indicate that the ATL-1 response is highly stereoselective. Also, a direct comparison of ATL-1 with native LXA4 and 15-epi-LXA 4 at equimolar concentrations (10 nM) in a representative experiment showed that ATL-1 > 15-epi-LXAt > LXA t in rank order of activity (e.g., 63.3 ⁇ 3.3, 59.8 ⁇ 1.8 and 38.1 ⁇ 2.0% inhibition, respectively).
  • VEGF is also an endothelial cell survival factor, thus promoting angiogenesis not only by stimulating cell proliferation but also by inhibiting endothelial cell apoptosis (17).
  • DNA fragments were quantitated (under Materials and Methods).
  • Endothelial cell migration is an essential component of the angiogenic process, providing directionality for the budding capillary toward the angiogenic stimulus (3). Therefore, endothelial migration was assessed with ATL.
  • VEGF (3 ng/ml) was added to the lower compartment of a chemotaxis chamber and cell migration across a 10- ⁇ m pore-size gelatin-coated filter was quantitated (Figure 2).
  • Results in Figure 2B showed that ATL-1, LXA t , 15-epi-LXA t and 15-R/S- methyl, LXA 4 (ATL-1 shown as representative) gave concentration-dependent inhibition of VEGF-stimulated HUVEC migration with a maximum level of inhibition (-45%) at 10 nM ATL.
  • the antiproliferative actions of native lipoxins were first found with the human lung adenocarcinoma cell line (23) and recently with human renal mesangial cells (24).
  • the actions of LX, ATL and stable analogs are transduced by a high affinity transmembrane receptor (ALXR) identified in several cell types (for a review, see Chiang et al. (25)).
  • AXR high affinity transmembrane receptor
  • LXA t In mesangial cells, LXA t interacts with its own high affinity receptor (i.e., ALXR) as well as with a subclass of peptido- leukotriene receptors (cysLTi), where LXA t is a partial agonist (24).
  • ALXR high affinity receptor
  • cysLTi peptido- leukotriene receptors
  • LXA 4 and its bioactive stable analogs effectively displace [ 3 H]LTD specific binding to vascular endothelial cells (26).
  • recent findings provide the first evidence that ATL specifically antagonizes LTD 4 specific binding at recombinant human cysLTi cloned from endothelial cells, as well as acts at specific LXA t receptors (21). Since ATL-1 proved to be a potent inhibitor of HUVEC proliferation ( Figures 1, 2 and 3), it was determined whether ATL affected angiogenesis in vivo.
  • FIG. 4B shows representative vascular casts from typical day 6 air pouch linings.
  • VEGF Figure 4B, bottom left panel
  • fluorescein isothiocyanate-dextran was used to visualize the vessels in this region.
  • LTB 4 another lipoxygenase pathway product
  • Figure 5 shows photomicrographs of the dorsal linings dissected at day 6. Again, profound angiogenesis was demonstrated with extensive vascular networks in VEGF-treated pouch (Figure 5, bottom left panel). Here too, treatment with ATL-1 (10 ⁇ g/pouch) gave striking reduction of VEGF-elicited vasculature, as exemplified by the lack of visible fine capillaries ( Figure 5, bottom right panel).
  • ATL-1 at this dose (10 ⁇ g/mouse i.v.) does not evoke apparent changes in mean arterial pressure, excluding a possible action of ATL-1 at the level of vascular tone.
  • LXA can stimulate vasodilation in certain vascular beds.
  • the present in vivo experiments were performed in separate series to evaluate histology and the presence of a vascular marker by using immunohistochemical staining of the murine air pouch with the vascular endothelial cell marker CD31 ( Figure 6).
  • Platelet/endothelial cell adhesion molecule- 1 (or CD31) is a member of the Ig superfamily that is strongly expressed at the endothelial cell-cell junction, is present on platelets as well as leukocytes, and is held to play a role in angiogenesis and in transendothelial migration of leukocytes.
  • Immunohistochemical staining for CD31 in the pouches showed that, in the VEGF-treated mice, strong specific endothelial cell staining was present and identified a prominent vascular network (Figure 6C). In contrast, a marked diminution of vessels was observed in VEGF-treated mice that were also treated with the LXA t analog ( Figure 6D).
  • ASA is thought to act, in part, via reduction of angiogenesis, which might be related to the ability of ASA to inhibit prostanoid biosynthesis (7). More recently, ASA was found to trigger a novel switch in eicosanoid biosynthesis as the acetylation of COX-2 enables the enzyme to produce 15R-HETE that is converted to 15-epi-lipoxins, also known as ATL, during cell-cell interactions in vitro and in vivo (11, 12, 14).
  • ATLs as well as their stable bioactive analogs are potent inhibitors of several key events in acute inflammation, such as PMN chemotaxis and transmigration across both endothelial and epithelial cells, as well as diapedesis from postcapillary venules (13, 14).
  • the analogs of ATL mimic both endogenous ATL and LX actions and were designed to resist rapid enzymatic inactivation in vivo.
  • Bioactive analogs of 15-epi-LXA ⁇ were also found to complete at both the ALXR on leukocytes and the cysLTi receptor present on vascular endothelial cells.
  • VEGF-induced proliferation 50.4 ⁇ 4.0
  • an aspirin -triggered- lipoxin, 15-epi-LXA analog is a potent inhibitor of angiogenesis and of endothelial cell proliferation in vivo.
  • 15-epi-lipoxins suggest a role for the aspirin-triggered lipoxin circuit (14) as a potential mechanism that can contribute to aspirin's recognized antiangiogenic and anti-inflammatory properties (2, 7, 10).
  • VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp. Cell Res. 247:495-504.

Abstract

La présente invention concerne des méthodes de prévention ou d'inhibition de l'angiogenèse. Cette méthode consiste à administrer, à un sujet qui en a besoin, une dose efficace de 15-épi-16-(para-fluoro)-phénoxy-lipoxine A4, LXA4, 15-épi-LXA4 ou 15-R/S-méthyle, LXA4 et de ces composés. Cet agent thérapeutique a pour effet de prévenir ou d'inhiber l'angiogenèse chez le sujet.
PCT/US2002/006404 2001-03-02 2002-03-01 Analogues de la lipoxine en tant qu'inhibiteurs de l'angiogenese WO2002070068A2 (fr)

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DK02721234T DK1406698T3 (da) 2001-03-02 2002-03-01 Lipoxinanaloger som nye inhibitorer af angiogenese
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EP02721234A EP1406698B1 (fr) 2001-03-02 2002-03-01 Analogues de la lipoxine en tant qu'inhibiteurs de l'angiogenese
JP2002569237A JP2005508282A (ja) 2001-03-02 2002-03-01 新規な脈管形成抑制剤としてのリポキシン類似物
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